Methods of treating estrogen receptor mediated conditions

Abstract

The present disclosure provides a method for treating an estrogen receptor mediated disease, disorder, or condition in a subject comprising administering to the subject a combination of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and ribociclib, or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims the priority and benefit of U.S. Application No. 63 / 413,475, filed on October 5, 2022, the entire content of which is hereby incorporated by reference. Background of the Invention

[0003] Breast cancer is the most commonly diagnosed cancer in women. Approximately 5% to 10% of cases are metastatic at the time of diagnosis, and nearly 30% of patients with early-stage disease will go on to relapse and develop metastatic disease. Reinert, T. and Barrios, C.H., Therapeutic Advances in Medical Oncology, 7(6), 304–320 (2015); Sini, V., Cinieri, S., Conte, P., Laurentiis, M.D., Leo, A.D., Tondini, C. and Marchetti, P., Critical Reviews in Oncology / Hematology, 100, 57–68 (2016). Endocrine therapy is the first-line treatment for advanced estrogen receptor-positive cancers. However, over time, most patients develop resistance to endocrine therapy. Alternative treatments exist, such as the selective estrogen receptor degrader fulvestrant, but it has limited potential due to poor bioavailability. Summary of the Invention

[0004] The present disclosure particularly provides methods for treating, stabilizing, or reducing the severity or progression of estrogen receptor-mediated diseases, disorders, and afflictions by administering an orally bioavailable estrogen receptor antagonist and an orally bioavailable CDK4 / 6 inhibitor.

[0005] In some embodiments, the present disclosure provides a method for treating an estrogen receptor-mediated disease in a subject, the method comprising administering to the subject a combination of a composition comprising Compound 1

[0006]

[0007] Compound 1

[0008] or a pharmaceutically acceptable salt thereof and a composition comprising ribociclib or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the present disclosure provides a kit comprising a composition comprising Compound 1

[0010]

[0011] A composition of ribociclib or a pharmaceutically acceptable salt thereof and a composition comprising ribociclib or a pharmaceutically acceptable salt thereof, optionally wherein the kit comprises a label indicating that Compound 1 and ribociclib can be used to treat estrogen receptor-mediated diseases, disorders, and conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1A is a graph showing the mean (SD) plasma concentration-time curve of 30 mg of Compound 1 as a single agent and in combination with 600 mg of ribociclib following a single oral dose.

[0013] Figure 1B is a graph showing the mean (SD) plasma concentration-time curve of 60 mg of Compound 1 as a single agent and in combination with 600 mg of ribociclib following a single oral dose.

[0014] Figure 1C is a graph showing the mean (SD) plasma concentration-time curve of 120 mg of Compound 1 as a single agent and in combination with 600 mg of ribociclib following a single oral dose.

[0015] Figure 2A is a graph showing the steady-state plasma concentration-time curve of 30 mg of Compound 1 in combination with 600 mg of ribociclib and the mean (SD) steady-state plasma concentration-time curve of 30 mg of Compound 1 as a single agent.

[0016] Figure 2B is a graph showing the steady-state plasma concentration-time curve of 60 mg of Compound 1 in combination with 600 mg of ribociclib and the mean (SD) steady-state plasma concentration-time curve of 60 mg of Compound 1 as a single agent.

[0017] Figure 3 is a graph showing the geometric mean (SD) plasma pharmacokinetic parameters of 600 mg of ribociclib as a single agent and in combination with three different doses of Compound 1 following a single oral dose.

[0018] Figure 4 is a graph showing the steady-state geometric mean (SD) plasma dose-normalized pharmacokinetic parameters of 600 mg of ribociclib as a single agent and in combination with two different doses of Compound 1. DETAILED EMBODIMENTS

[0019] The present disclosure particularly provides a method for treating an estrogen receptor-mediated disease in a subject, the method comprising administering a combination of a composition comprising compound 1 or a pharmaceutically acceptable salt thereof and a composition comprising ribociclib or a pharmaceutically acceptable salt thereof. In particular, the present disclosure encompasses the insight that certain synergistic effects can be achieved when compound 1 is combined with ribociclib in the treatment of estrogen receptor-mediated diseases, as compared to administering compound 1 or ribociclib alone.

[0020] Definitions

[0021] About: As used herein, the term "about" refers to a value similar to the recited value in the context. Generally, one of ordinary skill in the art familiar with the context will understand the relevant degree of difference covered by "about" in that context. For example, in some embodiments, the term "about" may cover a range of values within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the recited value. In some embodiments, "about" means ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1% of the recited value.

[0022] Administer: As used herein, the term "administer" generally refers to the administration of a composition to a subject or system, for example to effect the delivery of an agent that is the composition or is included in the composition or is otherwise delivered by the composition.

[0023] Agent: As used herein, the term "agent" refers to an entity (e.g., a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or a complex, combination, mixture or system thereof [e.g., a cell, tissue, organism]), or a phenomenon (e.g., heat, electric current or field, magnetic force or field, etc.).

[0024] Antagonist: As used herein, the term "antagonist" may refer to an agent or condition whose presence, level, degree, type or form is associated with a decrease in the level or activity of a target. An antagonist can include agents of any chemical class, including for example small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals and / or any other entity that exhibits relevant inhibitory activity. In some embodiments, an antagonist can be a "direct antagonist" as it binds directly to its target; in some embodiments, an antagonist can be an "indirect antagonist" as it exerts its effect by means other than direct binding to its target; e.g., by interacting with a regulator of the target, thereby altering the level or activity of the target). In some embodiments, an "antagonist" may be referred to as an "inhibitor".

[0025] Related: As used herein, two events or entities are "related" to each other if the existence, level, and / or form of one is associated with the existence, level, degree, type, and / or form of the other. For example, if the existence, level, and / or form of a particular entity (such as a polypeptide, genetic signature, metabolite, microorganism, etc.) is associated with the incidence and / or susceptibility of a disease, disorder, or condition (e.g., in a relevant population), then the particular entity is considered related to the particular disease, disorder, or condition. In some embodiments, two or more entities are physically "related" to each other if they interact directly or indirectly such that they are physically close to and / or remain physically close to each other. In some embodiments, two or more entities that are physically related to each other are covalently linked to each other; in some embodiments, two or more entities that are physically related to each other are not covalently linked, but rather are non-covalently associated, e.g., by hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0026] Biological sample: As used herein, the term "biological sample" generally refers to a sample obtained from or derived from a target biological source (e.g., a tissue or an organism or a cell culture) as described herein. In some embodiments, the target source includes an organism, such as an animal or a human. In some embodiments, the biological sample is or includes a biological tissue or fluid. In some embodiments, the biological sample can be or include bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; body fluids containing cells; free-floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph fluid; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washes or lavages, such as catheter lavages or bronchoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the obtained cells are or include cells from the individual from whom the sample was obtained. In some embodiments, the sample is a "primary sample" obtained directly from the target source by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluids (e.g., blood, lymph fluid, feces, etc.), etc. In some embodiments, it will be clear from the context that the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or by adding one or more agents). For example, filtration using a semipermeable membrane. Such a "processed sample" can include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, separation and / or purification of certain components, etc.

[0027] Biomarker: As used herein, the term "biomarker" (consistent with its use in the art) refers to an entity (or a form thereof) whose presence or level is associated with a particular biological event or state of interest such that it is considered a "marker" of said event or state. By way of example only, in some embodiments, a biomarker can be or include a marker of a particular disease state, or a marker of the likelihood that a particular disease, disorder or condition may develop, occur or recur. In some embodiments, a biomarker can be or include a marker of a particular disease or treatment outcome or the likelihood thereof. Thus, in some embodiments, a biomarker predicts a relevant biological event or state of interest, in some embodiments, a biomarker prognosticates a relevant biological event or state of interest, and in some embodiments, a biomarker diagnoses a relevant biological event or state of interest.

[0028] Combination therapy: As used herein, the term "combination therapy" refers to those situations in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents). In some embodiments, two or more regimens can be administered simultaneously; in some embodiments, such regimens can be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); in some embodiments, such agents are administered in an overlapping dosing regimen. In some embodiments, "administration" of a combination therapy can involve administering one or more agents or modalities to a subject who is receiving other agents or modalities in the combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily simultaneously), although in some embodiments, two or more agents or their active moieties can be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0029] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, situations, groups of conditions, etc. that may differ from each other but are similar enough to allow comparison between them, such that one of ordinary skill in the art will understand that conclusions can be reasonably drawn based on the observed differences or similarities. In some embodiments, comparable groups of conditions, environments, individuals or populations are characterized by a plurality of substantially identical characteristics and one or a small number of different characteristics. One of ordinary skill in the art will understand that, in context, what degree of consistency is required for two or more such agents, entities, situations, groups of conditions, etc. to be considered comparable in any given situation. For example, one of ordinary skill in the art will understand that environments, individuals or groups of populations are comparable to each other when characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results or observed phenomena obtained under or using different environments, individuals or groups of populations are caused by or indicative of changes in those varying characteristics.

[0030] Corresponds to: As used herein, the phrase "corresponds to" refers to a relationship between two entities, events, or phenomena that have sufficient characteristics to be reasonably comparable such that the "corresponding" attribute is evident. For example, in some embodiments, the term may be used with respect to a compound or composition to specify the position and / or identity of a structural element in the compound or composition by comparison to a suitable reference compound or composition. For example, in some embodiments, monomer residues in a polymer (e.g., amino acid residues in a polypeptide or nucleic acid residues in a polynucleotide) may be identified as "corresponding to" residues in a suitable reference polymer. For example, one of ordinary skill in the art will understand that, for simplicity, a standard numbering system based on a reference related polypeptide is typically used to specify residues in a polypeptide such that the amino acid "corresponding to" the residue at position 190, for example, need not actually be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue present at position 190 in the reference polypeptide; one of ordinary skill in the art readily understands how to identify the "corresponding" amino acid. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs that can be used to identify, for example, "corresponding" residues in polypeptides and / or nucleic acids according to the present disclosure, such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE.

[0031] Dosage form or unit dosage form: One of ordinary skill in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is an amount that is a unit dose (or an entire portion thereof) suitable for administration according to a dosing regimen, the amount of the unit dose having been determined to be related to the desired or beneficial outcome (i.e., related to a therapeutic dosing regimen) when administered to a relevant population. One of ordinary skill in the art understands that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0032] Dosing Regimen or Treatment Regimen: Those skilled in the art will understand that the terms "dosing regimen" and "treatment regimen" can be used to refer to a set of unit doses (usually more than one) that are typically administered to a subject separately at intervals of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each dose being spaced apart in time from the other doses. In some embodiments, the individual doses are spaced apart by the same length of time period; in some embodiments, the dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all the doses within the dosing regimen have the same unit dose amount. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is different from the first dose amount. In some embodiments, the dosing regimen includes a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is the same as the first dose amount. In some embodiments, when administered across a relevant population, the dosing regimen is associated with a desired or beneficial outcome (i.e., is a therapeutic dosing regimen).

[0033] Excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, and the like.

[0034] Improve, Increase or Decrease: As used herein, the terms "improve", "increase" or "decrease" or their grammatically equivalent comparative terms refer to a value relative to a comparable reference measurement. For example, in some embodiments, an evaluated value obtained with the agent of interest may "improve" relative to an evaluated value obtained with a comparable reference agent. Alternatively or additionally, in some embodiments, an evaluated value obtained in the subject or system of interest may "improve" relative to an evaluated value obtained in the same subject or system under different conditions (e.g., before or after an event such as the administration of the agent of interest) or in a different comparable subject (e.g., in a comparable subject or system different from the subject or system of interest in the presence of one or more indicators of a particular disease, disorder or affliction of interest, or after prior exposure to an affliction or agent, etc.).

[0035] Oral: As used herein, the phrases "oral administration" and "administered orally" have their ordinary meaning in the art and refer to the administration of a compound or composition through the oral cavity.

[0036] Parenteral: As used herein, the phrases "parenteral administration" and "administered parenterally" have their ordinary meaning in the art and refer to a mode of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0037] Patient or subject: As used herein, the term "patient" or "subject" refers to any organism to which the provided composition is administered or may be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. In some embodiments, the patient or subject has or is susceptible to one or more disorders or diseases. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or disease. In some embodiments, the patient or subject has been diagnosed with one or more disorders or diseases. In some embodiments, the patient or subject is receiving or has received a particular therapy for the diagnosis and / or treatment of a disease, disorder, or disease.

[0038] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dosage amount suitable for administration in a treatment regimen for the relevant subject (e.g., in an amount that has been shown to have a statistically significant probability of achieving a predetermined therapeutic effect upon administration) or in different, comparable subjects (e.g., in the presence of one or more indications of a target specific disease, disorder, or disease in a comparable subject or system different from the target subject or system, or upon prior exposure to a disease or agent, etc.). In some embodiments, the comparison terms refer to a statistically relevant difference (e.g., a prevalence and / or magnitude sufficient to achieve statistical relevance). In a given context, one of ordinary skill in the art will recognize or will be able to readily determine the degree and / or prevalence of the difference required or sufficient to achieve such statistical significance.

[0039] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0040] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle involved in carrying or transporting the subject compound from one organ or part of the body to another, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and / or polyanhydrides; and other non-toxic and compatible materials used in pharmaceutical formulations.

[0041] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in a pharmaceutical context, i.e., salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to: non-toxic acid addition salts, which are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (such as ion exchange). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In some embodiments, where appropriate, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having 1 to 6 carbon atoms, sulfonate, and arylsulfonate.

[0042] Prevent or prevention: As used herein, the terms "prevent" or "prevention," when used in connection with the occurrence of a disease, disorder, and / or affliction, refer to reducing the risk of developing a disease, disorder, and / or affliction and / or delaying the onset of one or more characteristics or symptoms of a disease, disorder, and / or affliction. Prevention can be considered complete when the onset of a disease, disorder, or affliction has been delayed for a predetermined period of time.

[0043] Reference: As used herein, the term "reference" describes a standard or control against which a comparison is made. For example, in some embodiments, an agent, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control agent, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially contemporaneously with the test or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Generally, as will be understood by those of skill in the art, the reference or control is determined or characterized under conditions or circumstances comparable to the evaluation conditions or circumstances. Those of skill in the art will understand when there is sufficient similarity to justify reliance on and / or comparison to a particular possible reference or control.

[0044] Small molecule: As used herein, the term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule having a size less than about 5 kilodaltons (kD). In some embodiments, the small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, the small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule is not a polymer.

[0045] In some embodiments, the small molecule does not contain a polymeric moiety. In some embodiments, the small molecule is not and / or does not contain a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, the small molecule is not and / or does not contain a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, the small molecule is not and / or does not contain a polysaccharide; for example, in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, the small molecule is not a lipid.

[0046] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule has biological activity. In some embodiments, the small molecule is detectable (e.g., contains at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0047] One of ordinary skill in the art reading this disclosure will understand that certain small molecule compounds described herein can be provided and / or used in any of a variety of forms, such as crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0048] One of ordinary skill in the art will understand that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules can be used in the form of individual enantiomers, diastereomers, or geometric isomers according to the present disclosure, or can be in the form of a mixture of stereoisomers; in some embodiments, such small molecules can be used in the form of a racemic mixture according to the present disclosure.

[0049] One of skill in the art will understand that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules can be used in the form of individual tautomers or in forms that interconvert between tautomeric forms according to the present disclosure.

[0050] One of skill in the art will understand that certain small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H substituting for H; 11 C, 13 C or 14 C substituting for 12 C; 13 N or 15 N substituting for 14 N; 17 O or 18 O substituting for 16 O; 36 Cl substituting for 35 / 37 Cl; 18 F substituting for 19 F; 131 I substituting for 127 I; etc.). In some embodiments, such small molecules can be used in one or more isotopically modified forms or mixtures thereof according to the present disclosure.

[0051] In some embodiments, a reference to a particular small molecule compound can refer to a specific form of the compound. In some embodiments, a particular small molecule compound can be provided and / or used in salt form (e.g., in the form of an acid addition salt or a base addition salt, depending on the compound); in some such embodiments, the salt form can be a pharmaceutically acceptable salt form.

[0052] In some embodiments, where the small molecule compound is a compound that exists or is found in nature, the compound can be provided and / or used in a form different from its form as it exists or is found in nature in accordance with the present disclosure. One of ordinary skill in the art will appreciate that in some embodiments, a formulation of a particular small molecule compound, when the absolute or relative amount of the compound or a particular form thereof contained therein is different from the absolute or relative (relative to another component of the formulation, including, for example, another form of the compound) amount present in a reference formulation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source), is distinct from the compound as it exists in the reference formulation or source. Thus, in some embodiments, for example, a formulation of a single stereoisomer of a small molecule compound can be considered a different form of the compound from the racemic mixture of the compound; a particular salt of a small molecule compound can be considered a different form from another salt form of the compound; a formulation of a compound form containing only one conformational isomer ((Z) or (E)) of a double bond can be considered a different form of the compound from another conformational isomer ((E) or (Z)) containing the double bond; a formulation in which one or more atoms are isotopes different from the isotopes present in the reference formulation can be considered a different form; and so on.

[0053] Therapeutic agent: As used herein, the phrase "therapeutic agent" generally refers to any agent that elicits a desired pharmacological effect when administered to a living organism. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect in an appropriate population as a whole. In some embodiments, the appropriate population can be a population of model organisms. In some embodiments, the appropriate population can be defined according to various criteria, such as a certain age group, gender, genetic background, pre-existing clinical condition, and the like. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, improve, relieve, inhibit, prevent one or more symptoms or characteristics of a disease, disorder, and / or affliction, delay its onset, reduce its severity, and / or reduce its incidence. In some embodiments, a "therapeutic agent" is an agent that has been or needs to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is an agent that requires a medical prescription for administration to humans.

[0054] Treatment: As used herein, the terms "treat", "treatment" or "treating" refer to any method for partially or completely alleviating, ameliorating, mitigating, suppressing, preventing a disease, disorder and / or affliction, delaying its onset, reducing its severity and / or reducing the occurrence of one or more of its symptoms or characteristics. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder and / or affliction. In some embodiments, treatment can be administered to a subject who exhibits only early signs of a disease, disorder and / or affliction, for example, for the purpose of reducing the risk of developing a pathology associated with the disease, disorder and / or affliction.

[0055] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to the amount of a substance (e.g., a therapeutic agent, composition and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent a disease, disorder and / or affliction and / or delay its onset when administered to a subject suffering from or susceptible to a disease, disorder and / or affliction. As will be appreciated by one of ordinary skill in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue. For example, an effective amount of a compound in a formulation for treating a disease, disorder and / or affliction is an amount that alleviates, ameliorates, mitigates, suppresses, prevents the disease, disorder and / or affliction, delays its onset, reduces its severity and / or reduces the occurrence of one or more of its symptoms or characteristics. In some embodiments, a therapeutically effective amount is administered as a single dose; in some embodiments, delivery of a therapeutically effective amount requires multiple unit doses.

[0056] Those skilled in the art will understand that the compounds mentioned herein can be enriched with one or more isotopes at any or all atoms at an isotope ratio higher than the naturally occurring one, such as but not limited to deuterium ( 2 H or D).

[0057] The compounds of the present invention or their pharmaceutically acceptable salts may contain chiral centers, which may be in the (R) or (S) configuration, or may contain a mixture thereof, unless otherwise specified. Accordingly, this application includes the stereoisomers of the compounds described herein, alone or in any proportion admixed, where applicable. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and isolated using conventional techniques, by reacting enantiomeric starting materials or by separating the isomers of the compounds of this application.

[0058] Methods for treating estrogen receptor-mediated diseases

[0059] The present disclosure particularly provides a method for treating estrogen receptor-mediated diseases, disorders and afflictions, the method comprising administering Compound 1 to a patient in need thereof

[0060]

[0061] or a pharmaceutically acceptable salt thereof and ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 and ribociclib are administered to the patient as separate compositions, each composition comprising one or more suitable pharmaceutically acceptable excipients.

[0062] The present disclosure encompasses the insight that when Compound 1 and ribociclib are co-administered to a patient suffering from an estrogen receptor-mediated disease, disorder or affliction, certain synergistic effects can be achieved. The claimed method of the invention can exhibit benefits over currently available therapeutic methods such as fulvestrant, since both Compound 1 and ribociclib are orally bioavailable and can be administered to the patient in any suitable form (including as capsules or tablets, etc.).

[0063] Estrogen receptor (“ER”) is involved in a variety of biological processes such as those related to the development of the female reproductive system, the maintenance of bone mass, the protection of cardiovascular and / or central nervous system components, etc. (see, e.g., Pearce and Jordan Crit. Rev. Onc / Hem 50:3, 2004; Heldring Phys. Rev. 87:905, 2007). ER has been implicated in a variety of cancers. In many tumors that express estrogen receptor (i.e., ER + tumors, also referred to herein as hormone-positive or HR+ tumors), active ERα signaling has been shown to drive cell proliferation (although ERβ signaling has been reported to be able to effect tumor-suppressive effects; see, e.g., Nilsson and Gustafson Clin. Pharmacol. Ther. 89:44, 2011). Typically, only 1% of the cells in a tumor (e.g., breast tumor) that stain positive for ER are classified as “ER + ”. Treatments that target ER are many ER +Standard treatments for cancer patients (see, e.g., Cardoso et al., Annals Onc., https: / / doi.org / 10.1093 / announc / mdmx036, 2017; Rugo et al., J. Clin. Oncol. 34:3069, 2016; Senkus et al., Annal Onc. 26:v8, 2015; Sareddy and Vadlamudi, Clin. J. Nat. Med, 13:801, 2015). For example, for patients with early breast cancer, recommended therapies typically include tumor resection, followed by ER-targeted therapy (e.g., as discussed below). For advanced breast cancer (including metastatic breast cancer), ER-targeted therapy is the mainstay.

[0064] In addition, the presence or development of certain ER mutations has been reported to affect the efficacy of various ER-targeted therapies (see, e.g., Jeselsohn et al., Nature Rev. Clin. Oncol. 12, 573, 2015; Gelsomino et al., Breast Cancer Res. Treat 157:253, 2016; Toy et al., 2013). Some particularly problematic mutations are those that “activate” one or more aspects of ER expression and / or function; some activating mutations have been reported to render the ER ligand-independent (i.e., constitutively active). For example, specific mutations in the ER ligand-binding domain (including D538G and Y537S) have been shown to constitutively activate the ER; other mutations (including deletions and / or fusions that remove the ligand-binding domain) can have similar effects (see, e.g., Li et al., Cell Repts 4:1116, 2013; Veeraraghavan et al., Breast Cancer Research and Treatment 158, 219–232, 2016; Veeraraghavan et al., Nature Comms 5:4577, 2014). Some reports suggest that up to 50% of women with metastatic breast cancer may have activating ER mutations detectable in circulating tumor DNA.

[0065] However, regardless of the mechanism of action of a particular agent, clinical experience to date has shown that incomplete effects (e.g., within an individual patient and / or across patient populations) and / or the development of resistance remain problems.

[0066] In some embodiments described herein, the estrogen receptor-mediated disease is cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer (e.g., breast cancer) has metastasized to another organ (e.g., brain, bone, lung, and / or liver). In some embodiments, the organ with metastasis is the subject's brain. In some embodiments, the organ with metastasis is the subject's bone. In some embodiments, the organ with metastasis is the subject's lung. In some embodiments, the organ with metastasis is the subject's liver.

[0067] In some embodiments, the subject has HR+ / HER2-metastatic breast cancer. In some embodiments, the subject has cancer that has metastasized to another organ (e.g., brain, lung, liver, and / or bone). In some embodiments, the subject has histologically or cytologically confirmed advanced or metastatic breast cancer (e.g., for which there is no standard treatment).

[0068] In some embodiments, the subject having the disease described herein has previously been administered endocrine therapy. In some embodiments, the subject has received at least 6 months of prior continuous endocrine therapy for locally advanced or metastatic breast cancer. In some embodiments, the subject has received no more than 2 prior hormonal regimens for advanced or metastatic disease.

[0069] In some embodiments, the subject having the disease described herein has previously been administered chemotherapy (e.g., chemotherapy for locally advanced or metastatic disease). In some embodiments, the subject has previously been administered no more than one chemotherapy regimen for locally advanced or metastatic breast cancer.

[0070] In some embodiments, the subject has previously received at least one of a CDK4 / 6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.

[0071] Compound 1

[0072] In some embodiments, the present disclosure recognizes the particular utility of Compound 1, which is a complete estrogen receptor antagonist. In some embodiments, as the term is used herein, a "complete estrogen receptor antagonist" is characterized by complete antagonism of the estrogen receptor with no or minimal residual estrogen receptor agonist activity. For example, it should be understood that a complete estrogen antagonist is an agent (e.g., a small molecule compound) that shows ER antagonism without ER agonism in one or more of an ERα protein level assay, an MCF-7 cell line assay, an Ishikawa cell line assay (measuring wild-type ER and certain mutants, including mutants lacking the AF1 and / or AF2 domains), and a rodent uterine weight gain assay. Generally, see WO 2017 / 059139. Alternatively or additionally, in some embodiments, a complete estrogen receptor antagonist has three characteristics: it (1) inhibits both activation function 1 (AF1) and activation function 2 (AF2), since complete antiestrogenic activity requires inactivation of both AF1 and AF2; (2) promotes ER degradation; and (3) lacks partial ER agonist activity observed with some other agents. Without being bound by theory, it should be understood that complete inhibition of both AF1 and AF2 is necessary for complete estrogen receptor activity, since mutations in the gene encoding estrogen receptor 1 allow activation of both AF1 and AF2 even in the absence of estrogen.

[0073] Given the importance of ER signaling in many cancers as well as certain cardiovascular, inflammatory, and neurodegenerative diseases, a great deal of effort has been devoted to developing therapeutic agents and modalities that target the ER. The terminology used to describe ER-targeting agents has a certain fluidity / flexibility, but various agents with different mechanisms have been developed and / or studied.

[0074] Currently, fulvestrant is the only approved therapy with each of the characteristics of the complete estrogen receptor antagonist described above. However, fulvestrant has many drawbacks, including poor oral bioavailability and inability to cross the blood-brain barrier.

[0075] Compound 1

[0076]

[0077] Overcomes the drawbacks of fulvestrant and is an orally bioavailable complete estrogen receptor antagonist ("CERAN"). Compound 1 is described as Compound B in WO 2017 / 059139 and is also known as (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The synthesis and certain properties of Compound 1 were reported in WO 2017 / 059139.

[0078] Compound 1 effectively competes with the endogenous active estrogen ligand 17-β estradiol for binding in the ligand-binding pocket. Compound 1 blocks estrogen-driven transcriptional activity, inhibits estrogen-driven breast cancer cell growth, and induces the degradation of ER. As a CERAN, Compound 1 both completely inactivates and degrades ER, and completely inactivates ER by inactivating the transcriptional activation functions of activation function 1 (AF1) and activation function 2 (AF2). Compound 1 robustly degrades estrogen receptor in ER+ cell lines. In vivo studies have shown that Compound 1 has no agonist activity in the uterus of immature ovariectomized mice and blocks estrogen-driven uterine weight gain. Previous therapies, such as traditional selective estrogen receptor degraders (SERDs) that only degrade ER or selective estrogen receptor modulators (SERMs) with mixed agonist and antagonist effects, cannot achieve the complete estrogen receptor antagonism achieved by Compound 1.

[0079] Unless otherwise specified, as used herein, "Compound 1" refers to Compound 1 in any available form, such as, for example, a salt form and / or a solid form. Thus, it should be understood that a reference to an amount of Compound 1 (e.g., mg) refers to the amount of Compound 1 in free base form. Thus, Compound 1 can be provided and / or utilized, for example, in the form of a salt of Compound 1 such that the amount of the salt (or other form) is an amount corresponding to the "free base equivalent" of Compound 1.

[0080] In some embodiments, a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof further comprises one or more pharmaceutically acceptable carriers or excipients. For example, the pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. According to general practice, such dosage forms may also contain other substances in addition to the inert diluent, for example, lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0081] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or with one or more of the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite; and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. The active compounds can also be in microencapsulated form with one or more of the excipients as described above.

[0082] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells having, for example, enteric coatings (i.e., buffering agents) and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also have compositions that cause the active ingredient to be released optionally in a delayed manner only or preferentially in a certain part of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0083] In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 90 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg.

[0084] In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 30 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg QD. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 30 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 60 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 90 mg. In some embodiments, Compound 1 is administered to a subject once daily (QD) in an amount of about 120 mg.

[0085] In some embodiments, Compound 1 is administered to a subject in a unit dosage form. In some embodiments, the unit dosage form is a capsule or a tablet. In some embodiments, the unit dosage form comprises from about 15 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form comprises from about 15 mg to about 100 mg of Compound 1. In some embodiments, the unit dosage form comprises from about 60 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form comprises about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of Compound 1. In some embodiments, the unit dosage form comprises about 15 mg of Compound 1. In some embodiments, the unit dosage form comprises about 30 mg of Compound 1. In some embodiments, the unit dosage form comprises about 60 mg of Compound 1. In some embodiments, the unit dosage form comprises about 90 mg of Compound 1. In some embodiments, the unit dosage form comprises about 120 mg of Compound 1. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0086] In some embodiments, the amount of the total daily dose of Compound 1 administered to the subject is from about 15 mg to about 360 mg per day (QD). In some embodiments, the total daily dose of Compound 1 administered to the subject is from about 30 mg to about 360 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is from about 30 mg to about 300 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is from about 30 mg to about 120 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is from about 60 mg to about 120 mg. In some embodiments, the amount of the total daily dose of Compound 1 administered to the subject is from about 15 mg to about 100 mg QD. In some embodiments, the amount of the total daily dose of Compound 1 administered to the subject is about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg QD. In some embodiments, the total daily dose of Compound 1 administered to the subject is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, the amount of the total daily dose of Compound 1 administered to the subject is about 30 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is about 60 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is about 90 mg. In some embodiments, the total daily dose of Compound 1 administered to the subject is about 120 mg.

[0087] In some embodiments, Compound 1 is administered to a subject once daily for a 28-day cycle. In some embodiments, Compound 1 is administered to a subject once daily for two 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily for three, four, five, or more 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily for six, seven, eight, nine, ten, eleven, twelve, or more 28-day cycles. In some embodiments, Compound 1 is administered to a subject once daily until the symptoms of the disease are no longer measurable. In some embodiments, Compound 1 is administered for the duration of the subject's life. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a dose holiday. As used herein, "dose holiday" refers to a period of time during which no agent (e.g., Compound 1) is administered to the subject. In some embodiments, the dose holiday is one day, one week, or one 28-day cycle. In some embodiments, Compound 1 is administered once daily for one or more 28-day cycles, followed by a dose holiday, and then the administration of Compound 1 once daily is resumed at the same dose level as before the dose holiday.

[0088] Ribociclib

[0089] Ribociclib is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. Ribociclib has the following structure:

[0090]

[0091] Ribociclib is also known by the following names: 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. Ribociclib is approved for use in combination with (i) an aromatase inhibitor as an initial endocrine-based therapy; or (ii) fulvestrant as an initial endocrine-based therapy or after disease progression in postmenopausal women or in men receiving endocrine therapy, for the treatment of hormone receptor-positive (e.g., HR+ or ER+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. The complete prescribing information for Ribociclib can be found in the label at www.accessdata.fda.gov / drugsatfda_docs / label / 2021 / 209092s008lbl.pdf, which is incorporated herein by reference in its entirety.

[0092] Ribociclib is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. These kinases are activated upon binding to D-cyclins and play a key role in signaling pathways that lead to cell cycle progression and cell proliferation. The cyclin D-CDK4 / 6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib reduced pRb phosphorylation, resulting in G1-phase arrest of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, in a rat xenograft model of human tumor cells, treatment with a single dose of ribociclib led to tumor volume reduction, which was associated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor-positive breast cancer xenograft models, the combination of ribociclib with an anti-estrogen (e.g., letrozole) led to increased tumor growth inhibition compared to each drug alone. In addition, the combination of ribociclib with fulvestrant led to tumor growth inhibition in estrogen receptor-positive breast cancer xenograft models.

[0093] In some embodiments, a composition comprising ribociclib or a pharmaceutically acceptable salt thereof is provided and / or utilized in any suitable pharmaceutical composition or dosage form. In some embodiments, a composition comprising ribociclib or a pharmaceutically acceptable salt thereof further comprises one or more pharmaceutically acceptable carriers or excipients. For example, the pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.

[0094] In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is provided and / or utilized as a film-coated tablet for oral use. In some embodiments, a tablet comprising ribociclib or a pharmaceutically acceptable salt thereof further comprises one or more of colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, magnesium stearate or microcrystalline cellulose. In some embodiments, a tablet comprising ribociclib or a pharmaceutically acceptable salt thereof is coated with a film coating comprising one or more of iron oxide black, iron oxide red, lecithin (soy), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide and xanthan gum.

[0095] Unless otherwise specified, as used herein, "ribociclib" refers to ribociclib in any available form, such as for example a salt form and / or a solid form. Thus, it should be understood that a reference to an amount of ribociclib (e.g., mg) means the amount of ribociclib in free base form. Thus, ribociclib can be provided and / or utilized, for example, in the form of a salt of ribociclib such that the amount of the salt (or other form) is an amount corresponding to the "free base equivalent" of ribociclib.

[0096] In some embodiments, ribociclib is provided and / or utilized in the form of a salt. For example, in some embodiments, ribociclib is provided and / or utilized in the form of ribociclib succinate:

[0097]

[0098] Ribociclib succinate is also known by the following name: 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1) butanedioate.

[0099] In some embodiments, ribociclib is administered to a subject in an amount of from about 200 mg to about 800 mg. In some embodiments, ribociclib is administered to a subject in an amount of from about 500 mg to about 700 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 600 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 400 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg.

[0100] In some embodiments, ribociclib is administered to a subject once daily (QD) in an amount of from about 200 mg to about 800 mg. In some embodiments, ribociclib is administered to a subject once daily (QD) in an amount of from about 500 mg to about 700 mg. In some embodiments, ribociclib is administered to a subject once daily (QD) in an amount of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In some embodiments, ribociclib is administered to a subject in an amount of about 600 mg QD. In some embodiments, ribociclib is administered to a subject in an amount of about 400 mg QD. In some embodiments, ribociclib is administered to a subject in an amount of about 200 mg QD.

[0101] In some embodiments, ribociclib is administered to a subject in a unit dosage form. In some embodiments, the unit dosage form is a capsule or a tablet. In some embodiments, the unit dosage form comprises from about 150 mg to about 250 mg of ribociclib. In some embodiments, the unit dosage form comprises about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg or about 800 mg of ribociclib. In some embodiments, the unit dosage form comprises about 200 mg of ribociclib. In some embodiments, the unit dosage form comprises about 254.4 mg of ribociclib succinate. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0102] In some embodiments, the amount of the total daily dose of ribociclib administered to the subject is from about 200 mg to about 800 mg. In some embodiments, the total daily dose of ribociclib administered to the subject is from about 500 mg to about 700 mg. In some embodiments, the amount of the total daily dose of ribociclib administered to the subject is about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg or about 800 mg. In some embodiments, the total daily dose of ribociclib administered to the subject is about 600 mg. In some embodiments, the total daily dose of ribociclib administered to the subject is about 400 mg. In some embodiments, the total daily dose of ribociclib administered to the subject is about 200 mg.

[0103] In some embodiments, ribociclib is administered once daily to the subject for 21 days within a 28-day cycle (i.e., once daily for 21 days followed by a 7-day drug-free period).

[0104] Combination therapy

[0105] The present disclosure encompasses the recognition that combinations of certain agents can be beneficially used to fully antagonize estrogen receptors. Thus, in some embodiments, the present disclosure provides a method of treating a subject having an ER-related disorder (e.g., cancer or breast cancer), the method comprising administering a combination of Compound 1 or a pharmaceutically acceptable salt thereof and ribociclib or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the present disclosure provides a combination therapy comprising administering Compound 1 and ribociclib. In some embodiments, the present disclosure encompasses the insight that certain synergistic effects can be achieved when Compound 1 is combined with ribociclib in the treatment of estrogen receptor-mediated diseases, as compared to administering Compound 1 or ribociclib alone.

[0107] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily a combination of from about 15 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof and from about 200 mg to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily a combination of from about 30 mg to about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof and 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof and 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof and 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof and 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition, the method comprising administering to a subject once daily 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof and 600 mg of ribociclib or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, Compound 1 is administered daily for a 28-day cycle, and ribociclib is administered daily for 21 days of a 28-day cycle (i.e., the same 28-day cycle). In some embodiments, Compound 1 and ribociclib are administered for one, two, three, four, five, or more 28-day cycles.

[0109] It is to be understood that Compound 1 and ribociclib may be administered simultaneously or separately. For example, in some embodiments, Compound 1 and ribociclib are administered simultaneously. In some embodiments, Compound 1 and ribociclib are administered at approximately the same time each day (e.g., for the first 21 days of a 28-day cycle). In some embodiments, ribociclib is administered before Compound 1. In some embodiments, ribociclib is administered after Compound 1.

[0110] In some embodiments, the present disclosure provides a method that includes administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., according to the regimens provided herein) to a subject who has received or is receiving ribociclib. In some embodiments, the present disclosure provides a method that includes administering ribociclib (e.g., according to the regimens provided herein) to a subject who has received or is receiving compound 1.

[0111] In some embodiments, the present disclosure provides an improvement to a method of treating a disease, disorder, or condition that includes the combined administration of compound 1 or a pharmaceutically acceptable salt thereof and ribociclib, the improvement including administering from about 30 mg to about 120 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement further includes administering about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement includes administering 30 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement includes administering 60 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement includes administering 90 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement includes administering 120 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the methods described herein further include administering letrozole or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein further include administering about 2.5 mg of letrozole or a pharmaceutically acceptable salt thereof.

[0113] Kit

[0114] In some embodiments, the present disclosure provides a medicine box, the medicine box comprising one or more compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, and one or more compositions comprising ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box comprises a composition containing from about 30 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition containing from about 200 mg to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box comprises a composition containing about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition containing about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box comprises a composition containing about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition containing about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box comprises a composition containing about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition containing about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box comprises a composition containing about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition containing about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the medicine box further comprises packaging material, the packaging material comprising a label that indicates that Compound 1 and ribociclib are useful for treating estrogen receptor-mediated diseases, disorders, or conditions.

[0115] Example

[0116] Example 1. Phase 1b Open-Label Multicenter Study of the Combination of Compound 1 and the CDK4 / 6 Inhibitor Ribociclib in Adult Subjects with Advanced and / or Metastatic HR-Positive, HER2-Negative Breast Cancer

[0117] This example provides a two-part Phase 1b open-label study of the combination of Compound 1 and ribociclib.

[0118] The study aims to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and / or recommended Phase 2 dose (RP2D); and to characterize the safety and pharmacokinetic (PK) profiles of the combination of Compound 1 and ribociclib in adult subjects with hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Subjects will receive treatment and will be evaluated over 28-day cycles.

[0119] This example consists of two parts:

[0120] Part 1 (Dose Escalation): This part will evaluate the safety and pharmacokinetics (and determine the RP2D) of a series of doses of Compound 1 administered orally (PO) once daily (QD) to subjects in combination with 600 mg of ribociclib administered QD PO. The dose escalation study design will include cohorts of 3 to 6 evaluable subjects who will be recruited sequentially and monitored for DLT during the first cycle of study treatment. In the cohort safety review, PK and safety events will be reviewed, and DLT observations may be extended to 2 cycles.

[0121] Part 2 (Dose Expansion): This part of the study will further evaluate the safety and pharmacology of the combination of Compound 1 at the RP2D with ribociclib and provide an exploratory estimate of the anti-tumor activity of the combination.

[0122] The objectives of Part 1 (Dose Escalation) of the study are as follows:

[0123] Primary Objectives

[0124] · Identify the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and / or RP2D when Compound 1 is administered in combination with ribociclib.

[0125] · Evaluate the safety and tolerability when Compound 1 is administered in combination with ribociclib.

[0126] · Evaluate the PK of Compound 1 and ribociclib when administered in each combination.

[0127] Secondary Objectives

[0128] · Preliminarily evaluate the anti-tumor activity (ORR, defined as confirmed complete response [CR] + confirmed partial response [PR]) when Compound 1 is administered in combination with ribociclib, as evaluated by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

[0129] · Estimate the CBR (CR + PR + SD ≥ 24 weeks) when Compound 1 is administered in combination with ribociclib.

[0130] · Estimate the duration of response (DoR) of Compound 1 in subjects with HR+ / HER2− metastatic or locally advanced breast cancer without evidence of CNS metastases who have progressed after receiving at least 1 hormonal therapy regimen in the metastatic or locally advanced setting.

[0131] Exploratory Objectives

[0132] · Evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in plasma and ctDNA.

[0133] · Correlate the biomarkers of ERα and PR expression with the clinical activity of Compound 1.

[0134] The objectives of Part 2 (dose expansion) of the study are described as follows:

[0135] Primary objectives

[0136] · Characterize the safety and tolerability of Compound 1 at the RP2D when administered in combination with ribociclib.

[0137] · Characterize the PK of Compound 1 and ribociclib at the RP2D.

[0138] Secondary objectives

[0139] · Preliminarily evaluate the anti-tumor activity (ORR, defined as confirmed complete response [CR] + confirmed partial response [PR]) of Compound 1 when administered in combination with ribociclib as evaluated by the investigator using RECIST v1.1.

[0140] · Estimate the CBR of Compound 1 in subjects with HR+ / HER2− metastatic or locally advanced breast cancer without evidence of CNS metastasis who have progressed after receiving at least 1 hormonal therapy regimen in the metastatic or locally advanced setting.

[0141] · Estimate the duration of response (DoR) of Compound 1 in subjects with HR+ / HER2− metastatic or locally advanced breast cancer without evidence of CNS metastasis who have progressed after receiving at least 1 hormonal therapy regimen in the metastatic or locally advanced setting.

[0142] Exploratory objectives

[0143] · Evaluate the pharmacodynamic effects of treatment with Compound 1 on biomarkers in plasma and ctDNA.

[0144] · Correlate the biomarkers of ERα and PR expression with the clinical activity of Compound 1.

[0145] The endpoints of Part 1 (dose escalation) of the study are:

[0146] Primary endpoints

[0147] · The incidence and severity of DLT.

[0148] · The MTD and / or RP2D of Compound 1 when administered in combination with ribociclib.

[0149] · The incidence and severity of TEAE and SAE as evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE, v5.0).

[0150] · Plasma levels of Compound 1 (and potential metabolites) and ribociclib are determined at pre-specified time intervals to establish PK parameters, including maximum concentration (C max max), minimum concentration (C min min), time to reach maximum concentration (T max max), area under the curve (AUC), half-life (t 1 / 2 1 / 2) and trough concentration of Compound 1 at steady state.

[0151] Secondary endpoints

[0152] · ORR as determined by assessment of tumor response using RECIST 1.1.

[0153] · CBR as defined by the percentage of subjects with CR + PR + SD ≥ 24 weeks in subjects without evidence of CNS metastases.

[0154] · Duration of response (DoR) and DoR compared to the previous endocrine therapy.

[0155] Exploratory endpoints

[0156] · Explore candidate biomarkers in ctDNA before and after treatment (such as mutESR1, PIK3CA variants, etc.).

[0157] · Exploratory analysis of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the sponsor

[0158] · Percentage of Ki67 in archived or fresh biopsy samples obtained prior to C1D1.

[0159] · Quantitative ERα and PR (percentage and Allred score) in biopsy samples obtained from archived or fresh biopsy samples prior to C1D1.

[0160] The endpoints for Part 2 (dose expansion) of the study are:

[0161] Primary endpoints

[0162] · Incidence and severity of TEAE and SAE as evaluated using NCI CTCAE v 5.0.

[0163] · Plasma levels of Compound 1 (and potential metabolites) and ribociclib are determined at pre-specified time intervals to establish PK parameters, including maximum concentration (Cmax), minimum concentration (Cmin), time to reach maximum concentration (Tmax), area under the curve (AUC), half-life (t 1 / 2 1 / 2) and trough concentration of Compound 1 at steady state.

[0164] Secondary endpoints

[0165] · The ORR determined by evaluating tumor response assessment using RECIST 1.1.

[0166] · CBR as defined by the percentage of subjects with CR + PR + SD lasting ≥ 24 weeks among subjects without evidence of CNS metastasis.

[0167] · DoR, time to progression, and progression-free survival (PFS) in subjects without evidence of CNS metastasis.

[0168] Exploratory endpoints

[0169] · Explore candidate biomarkers in ctDNA (such as mutESR1, PIK3CA variants, etc.) before and after treatment with Compound 1.

[0170] · Exploratory analysis of metabolites of Compound 1 in plasma may also be conducted, and if so, the results of those analyses will be reported separately by the sponsor.

[0171] · Percentage of Ki67 in archived or fresh biopsy samples obtained before C1D1.

[0172] · Quantitative ERα and PR (percentage and Allred score) in biopsy samples obtained from archived or fresh samples before C1D1.

[0173] Inclusion criteria

[0174] Subjects eligible to participate in the study must meet all of the following criteria:

[0175] 1. Females or males aged ≥ 18 years.

[0176] 2. Willing and able to participate in and comply with all study requirements and provide a signed and dated informed consent form before starting any study procedures.

[0177] 3. Locally advanced or MBC confirmed by histology or cytology, for which there is no standard treatment.

[0178] 4. HR+ / HER2- disease, as determined by local acceptable standards using local pathology reports in the most recently obtained archived tumor tissue samples from metastatic sites.

[0179] 5. Evaluable disease (measurable and non-measurable).

[0180] a. Measurable disease, i.e., at least 1 measurable lesion according to RECIST 1.1 (lesions at previously irradiated sites can only be counted as target lesions if there are clear signs of significant progression since irradiation).

[0181] 6. Have received prior continuous endocrine therapy for locally advanced or metastatic breast cancer for at least 6 months.

[0182] 7. Life expectancy ≥ 6 months, as judged by the investigator.

[0183] 8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

[0184] 9. Women of childbearing potential must be willing to adhere to highly effective contraception:

[0185] a. Highly effective contraceptive methods include:

[0186] i. Total abstinence (when this is in line with the subject's preferences and usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, symptothermal method, post-ovulation method, etc.) and withdrawal are unacceptable contraceptive methods.

[0187] ii. Have had female sterilization (bilateral oophorectomy, with or without hysterectomy) or total hysterectomy or tubal ligation at least 6 weeks before receiving study treatment. In the case of oophorectomy only, only when the reproductive status of the woman is confirmed by follow-up hormonal level assessment.

[0188] iii. Male partner sterilization (at least 6 months before screening). For female subjects in the study, the male partner who has had a vasectomy should be the only partner of the subject, and the success of the vasectomy must be medically confirmed according to local practice.

[0189] iv. Placement of a non-hormonal intrauterine device (IUD).

[0190] b. In addition, women of reproductive potential must meet all of the following criteria:

[0191] i. Not pregnant, as confirmed by a negative serum pregnancy test (β-human chorionic gonadotropin) before starting study treatment

[0192] ii. Not breastfeeding

[0193] c. A female subject is considered to have reproductive potential unless she:

[0194] i. Is ≥ 60 years of age

[0195] ii. Has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy

[0196] iii. Has documented ovarian failure (serum estradiol and follicle-stimulating hormone levels)

[0197] iv. Menopause (amenorrhea ≥ 12 months), with concurrent discontinuation of drugs that interfere with ovarian function

[0198] 10. Male subjects must be willing to adhere to highly effective contraception. The highly effective contraception method must include one of the following criteria:

[0199] a. Successful vasectomy

[0200] b. For subjects who have not had a successful vasectomy and are partners of women with reproductive potential, their partners should comply with any of the following:

[0201] i. Hormonal contraception + male subject uses a condom with spermicide

[0202] ii. IUD (hormonal or non-hormonal)

[0203] iii. Depo Provera + male subject uses a condom with spermicide

[0204] 11. Premenopausal or perimenopausal female subjects must be willing to take a luteinizing hormone-releasing hormone (LHRH) agonist ≥ 2 weeks before the first study drug.

[0205] 12. No proton pump inhibitor (PPI) has been used within 7 days before the first study drug administration, and the subject agrees to avoid PPI therapy during the study duration.

[0206] 13. Subjects must not have received prior endocrine or targeted therapy within ≤ 2 weeks before the first study drug administration.

[0207] 14. Subjects must not have received prior fulvestrant, chemotherapy, antibody therapy, targeted therapy, or investigational therapy within ≤ 4 weeks before the first study drug administration.

[0208] 15. Prior radiotherapy must be completed at least 2 weeks before the first study drug administration, and the toxicity recovery is ≤ Grade 1 (except for alopecia).

[0209] 16. Major surgery and recovery must be completed at least 4 weeks before the first dose of the study drug is administered.

[0210] 17. Except for alopecia, any toxicity from prior therapy must resolve to ≤ Grade 1 or baseline (as defined by NCI CTCAE v5.0) before the first study drug administration.

[0211] 18. If subjects with brain metastases meet all of the following criteria, they are eligible to participate in the study:

[0212] a. The brain metastases have been treated, or do not require treatment at the time of study enrollment, or are unlikely to require treatment during the study.

[0213] b. Dexamethasone had been discontinued before the first study drug administration or the patient was taking a stable dose of dexamethasone ≤ 2 mg daily (or an alternative steroid administered at a level equivalent to ≤ 2 mg daily) for 4 weeks.

[0214] 19. Having the following laboratory values within 28 days before the first study drug administration:

[0215] a. Serum creatinine ≤ upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73m² according to the MDRD formula 2 ;

[0216] b. Total bilirubin ≤ 1.5 × ULN, unless there is a history of Gilbert syndrome, in which case total bilirubin should be ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN;

[0217] c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if there is liver involvement due to tumor;

[0218] d. Hemoglobin ≥ 9.0 g / dL within 4 weeks before the first dose of the study drug is administered and no red blood cell (RBC) transfusion is required;

[0219] e. Platelet count ≥ 100 × 10 9 cells / L;

[0220] f. Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 cells / L (no hematopoietic growth factors were used within 3 weeks before the first dose administration);

[0221] g. Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 × ULN, and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. If on long-term anticoagulation, PT and aPTT must be within the therapeutic range.

[0222] 20. Standard 12-lead ECG values defined as the average of three ECGs:

[0223] a. QTcF (QT interval corrected for heart rate using Fridericia's correction method) < 450 milliseconds at screening.

[0224] b. Mean resting heart rate is 50 to 90 beats per minute (bpm) (determined based on the ECG).

[0225] 21. Have received no more than 2 prior hormonal regimens for advanced or metastatic disease. Combinations of prior hormonal regimens with CDK4 / 6 inhibitors are permitted.

[0226] 22. Have received no more than 1 prior chemotherapy regimen for advanced or metastatic disease.

[0227] 23. The following laboratory values are within the normal range or corrected to the normal range within 24 hours of the first study drug administration by supplements:

[0228] a. Potassium

[0229] b. Magnesium

[0230] c. Total calcium (corrected for serum albumin)

[0231] 24. Left ventricular ejection fraction is greater than 50% as determined by MUGA or echocardiogram.

[0232] Exclusion Criteria

[0233] Subjects meeting any of the following exclusion criteria will not be eligible to participate in the dose escalation or dose expansion part of the study:

[0234] 1. Prior or concurrent malignancy, as determined by the medical monitor, whose natural history or treatment may interfere with the safety or efficacy assessment of the study protocol.

[0235] 2. Clinically significant, uncontrolled heart disease and / or cardiac repolarization abnormalities, including any of the following:

[0236] a. Myocardial infarction, angina, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to the first study drug administration.

[0237] b. Documented cardiomyopathy.

[0238] c. Family history of long QT syndrome or idiopathic sudden death or congenital long QT syndrome or risk factors for torsades de pointes (TdP), including uncorrected hypocalcemia, hypokalemia, or hypomagnesemia; history of heart failure; or history of clinically significant / symptomatic bradycardia.

[0239] d. Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-degree atrioventricular block (e.g., bifascicular block, Mobitz type II, and third-degree atrioventricular block).

[0240] e. Uncontrolled systolic blood pressure > 160 or < 90 mmHg.

[0241] 3. History of cerebrovascular disease within 6 months prior to the first administration of the study drug.

[0242] 4. History of pulmonary embolism or deep vein thrombosis within the past 6 months, or increased risk of thrombosis in the subject as determined by the investigator. (Subjects on long-term anticoagulation regimens are permitted.)

[0243] 5. History of pneumonia or interstitial lung disease (ILD). (Chest computed tomography [CT] scans performed for tumor assessment purposes prior to the start of study treatment should be reviewed to confirm the absence of relevant pulmonary complications.)

[0244] 6. Leptomeningeal disease or spinal cord compression.

[0245] 7. History or persistent gastrointestinal (GI) conditions that may affect the absorption of oral therapeutic agents (such as active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery, including gastrectomy, and including difficulty swallowing capsules).

[0246] 8. Known human immunodeficiency virus (HIV) infection.

[0247] 9. Known clinically significant liver history, meeting Child-Pugh class B or C, including active viral hepatitis or other hepatitis (e.g., hepatitis B or C virus), current alcohol abuse, or cirrhosis.

[0248] 10. History of severe skin reactions such as Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms.

[0249] 11. Requirement for antimicrobial therapy or clinically significant active infection.

[0250] 12. Clinically significant comorbidities such as active infection, mental illness, or any other disorder that may affect the subject's ability to participate in the study or may otherwise confound the study results.

[0251] 13. Currently receiving any of the following medications and unable to discontinue them 7 days prior to the start of treatment:

[0252] a. Concomitant medications, herbal supplements, grapefruit and its juice, and / or Seville oranges and their juice, which are strong inducers or inhibitors of cytochrome P450 (CYP) 3A4 / 5.

[0253] b. Medications with a narrow therapeutic window and primarily metabolized by CYP3A4 / 5.

[0254] 14. History of allergic reactions attributable to compounds with a chemical composition similar to any of the study drugs.

[0255] 15. Currently receiving or having received systemic corticosteroids ≤ 2 weeks before starting the study drug, or not fully recovered from the adverse reactions of such treatment.

[0256] a. Note: The following uses of corticosteroids are permitted:

[0257] i. Systemic corticosteroids with a short duration (< 5 days).

[0258] ii. Topical application for any duration (e.g., for rash).

[0259] iii. Inhaled sprays (e.g., for obstructive airway diseases).

[0260] iv. Eye drops or local injections (e.g., intra-articular).

[0261] 16. Currently receiving concomitant medications that have a risk of prolonging the QT interval and / or are known to cause TdP, and unable to discontinue or replace with a safe alternative (e.g., within 5 half-lives or 7 days before starting the study drug).

[0262] 17. Unable to determine the QTcF of the subject.

[0263] Number of planned subjects

[0264] The number of planned subjects in each part is provided below:

[0265] Part 1 (Dose Escalation): Approximately 9 to 18 subjects are planned to be enrolled; the exact number of subjects to be enrolled depends on the dose level at which DLT is observed. Subjects in Part 1 (Dose Escalation) who stop the study before completing Cycle 1 (C1) for reasons other than DLT will be replaced.

[0266] Part 2 (Dose Expansion): Twelve subjects will be enrolled in the dose expansion part of the study. Subjects in Part 2 (Dose Expansion) who withdraw from the study before completing at least 2 treatment cycles and at least 1 disease response assessment after baseline will be replaced.

[0267] Therefore, a maximum of 30 subjects will be enrolled in this study.

[0268] Study treatment

[0269] In this study, all subjects will receive the combination of Compound 1 and ribociclib.

[0270] Subjects should take Compound 1 capsules PO QD on an empty stomach at approximately the same time each day. Subjects should fast for 2 hours before the administration of Compound 1 and remain fasting, except for water allowed for taking the study drug, until 1 hour after dosing. The cycle will be repeated every 4 weeks (28 days) with continuous dosing of Compound 1.

[0271] Part 1 (Dose Escalation)

[0272] Cohorts of 3 to 6 subjects will be recruited at each Compound 1 dose level, and each subject will participate in only 1 cohort. Subjects at each dose level will be treated and observed for DLT until the end of the first cycle. In the cohort safety review, PK and safety events will be reviewed, and DLT observations may be extended to 2 cycles.

[0273] Based on the DLT observations in Cycle 1, 3+3 dose escalation will be followed. Cohorts of 3 to 6 subjects will be treated at each dose level. Three subjects can be recruited simultaneously at each dose level of the study. The decision to include a new subject in the current, next highest, or next lowest dose level is based on the available data at the time of inclusion of the new subject. If 2 or more DLTs are observed at a given dose level, the dose level will be decreased. After at least 3 subjects have completed Cycle 1, the decision to escalate to the next highest dose level will be made by the study personnel and sponsor representatives at the cohort review meeting. Intra-subject dose escalation is not allowed.

[0274] The maximum dose of Compound 1 to be administered will be 120 mg QD.

[0275] The dose escalation of Compound 1 will be conducted according to the following dosing schedule:

[0276]

[0277] Dose-Limiting Toxicity

[0278] During C1, the occurrence of DLT in subjects will be evaluated, where DLT is a TEAE defined by the protocol and graded by the investigator according to NCI CTCAE v5.0, and the investigator considers it to be at least possibly related to Compound 1. For each dose group, TEAEs meeting the DLT definition will be described separately. In the cohort safety review during dose escalation, PK and safety events will be reviewed, and DLT observations may be extended to 2 cycles.

[0279] Multiple concurrent TEAEs in an individual subject meeting the DLT definition will be considered as a single DLT.

[0280] Subjects must receive at least 75% of the planned dose of Compound 1 (at least 21 out of 28 doses) in C1 to evaluate the determination of DLT. Subjects who receive less than 75% of the planned dose for reasons other than DLT will be replaced. (Subjects who receive <75% of the planned dose in C1 will be evaluated in the overall safety analysis but not for dose escalation purposes.) In such cases, replacement subjects may be recruited to receive Compound 1 at the same starting dose as the subject who withdrew early.

[0281] Definition of MTD or RP2D

[0282] To define the MTD and / or RP2D of Compound 1, subjects will be evaluated based on the actual starting dose of Compound 1 during C1. For most subjects, this will be the dose cohort to which they are assigned.

[0283] The MTD is defined as the highest feasible dose tested in which <33% (i.e., ≤1 out of 6) of the subjects experienced DLT.

[0284] The RP2D will be determined after reviewing all available safety and PK data.

[0285] At least one laboratory or vital sign measurement obtained after at least one dose of study drug administration is required for inclusion in the analysis of specific safety parameters. Baseline measurements are also required to assess changes relative to baseline.

[0286] Duration of treatment

[0287] In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive up to 1 year of study treatment at the discretion of the investigator and up to more than 1 year of study treatment with the consent of the investigator and the sponsor. Subjects who discontinue Compound 1 must also discontinue ribociclib within the context of this protocol.

[0288] Reference therapy, dose, route, and protocol

[0289] Ribociclib

[0290] According to the prescribing information, all subjects will receive the combination of Compound 1 and ribociclib at a fixed dose of 600 mg QD for 21 consecutive days in the first 28-day cycle. Subjects should take their ribociclib dose at approximately the same time each day after the administration of Compound 1.

[0291] Evaluation criteria

[0292] Safety: Safety and tolerability will be evaluated by clinical review of all relevant parameters including AE, DLT, laboratory values, ECG results, and vital signs.

[0293] Pharmacokinetics: Pharmacokinetic parameters for each analyte (Compound 1 and ribociclib) in the PK analysis set will be determined using standard compartmental or non-compartmental methods.

[0294] Pharmacodynamics: Pharmacodynamic evaluation will be performed by assessing ctDNA before and after treatment. ESR1 mutations in ctDNA and other pathways important for ER activity will be evaluated.

[0295] Efficacy: Radiological and / or physical assessments of malignancies will be performed at screening / baseline (within 28 days before the first study drug administration) and after every 2 cycles. After the C8 radiological assessment, subjects who have been determined to have derived clinical benefit from the study treatment may reduce the frequency of radiological and physical assessments of malignancies to once every 3 months. The investigator will use RECIST v1.1 to evaluate ORR and CBR, as determined by the subject's best tumor response, duration of response, and time to progression. In subjects who achieve PR or CR at the second examination ≥4 weeks after the initial response determination, additional imaging studies and tumor measurements will be performed.

[0296] Statistical Methods

[0297] The data collected in this study will be presented using summary tables, data listings, and graphs. Categorical data will be summarized using contingency tables (frequencies and percentages). For continuous data, summary statistics of mean, standard deviation, median, minimum, and maximum will be presented. Baseline is defined as the last assessment before the first study treatment administration.

[0298] Safety Analysis: Safety data from Part 1 (dose escalation) will be summarized by dose cohort. Safety data from Part 2 (dose expansion) will also be summarized. Safety will be evaluated by summary of AEs, laboratory test results, vital signs, and ECOG PS.

[0299] Adverse events will be classified using MedDRA by system organ class and preferred terms, and severity will be classified using the CTCAE 5.0 criteria. All collected AE data will be listed. All SAEs will also be listed. All TEAEs, regardless of attribution, will be summarized by cohort. Changes in hematological, chemical, and other laboratory values will be descriptively summarized for each planned protocol assessment time point. Results of vital signs (blood pressure, pulse, respiration, and temperature) will be descriptively summarized for each planned protocol time point. ECOG performance status transition tables will be provided by cohort and planned visit. Analysis of ECG results will be based on subject baseline and treatment ECG data in the safety analysis set.

[0300] Exploratory Efficacy Analysis: Efficacy and biomarker analyses will be conducted for the FAS and the efficacy analysis set populations. The results of these analyses for the overall population will be presented according to mutESR1 status and whether the subject has received prior CDK4 / 6 inhibitor therapy. For Phase 1, descriptive summaries will be provided by cohort. The ORR (CR+PR) will be estimated in the dose expansion part. The estimated value of the ORR will be accompanied by a two-sided 95% exact CI. The ORR will be determined using RECIST v1.1. The CBR (CR+PR+SD>24 weeks) will be estimated and will be accompanied by a two-sided 95% exact CI. All CRs and PRs included in the ORR and CBR are confirmed responses. The objective response duration will be calculated for subjects who achieve a CR or PR. For such subjects, the objective response duration is defined as the number of days from the start date of the PR or CR (whichever response was achieved first) to the first date of objectively documented disease progression. The investigators will determine disease progression using RECIST v1.1.

[0301] Pharmacokinetic Analysis: Pharmacokinetic parameters for each analyte (Compound 1 and ribociclib) in the PK analysis set will be determined using standard compartmental or non-compartmental methods. The analyte concentrations for each cohort for each cycle and each day will be summarized using appropriate descriptive statistics (e.g., N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation [CV]%, geometric mean, and CV associated with the geometric mean).

[0302] Biomarker Analysis: Descriptive statistics will be used primarily to summarize the biomarker data generated in this study. For continuous variables, the number of subjects with non-missing data, mean, standard error or standard deviation, median, 25th percentile (first quartile), 75th percentile (third quartile), minimum, and maximum will be presented. For discrete data, frequency and percentage distributions will be presented.

[0303] Example 2. Data from a Phase 1b open-label multicenter study of the combination of Compound 1 with the CDK4 / 6 inhibitor ribociclib in adult subjects with advanced and / or metastatic HR-positive, HER2-negative breast cancer

[0304] This example reports a phase 1b open-label 2-part study of the combination of compound 1 and ribociclib. This example includes participants with evaluable HR+, HER2− advanced or metastatic breast cancer, ≤2 prior endocrine therapies (prior CDK 4 / 6 inhibitors permitted), and ≤1 prior line of chemotherapy. Participants were administered escalating doses of compound 1 30, 60, and 120 mg orally (PO) once daily (QD) in combination with the approved dose of ribociclib 600 mg PO QD (days 1–21 of a 28-day cycle) in a 3 + 3 design to identify the recommended phase 2 dose (RP2D). The dose expansion phase evaluated additional safety and PK parameters as well as antitumor activity of the combination of compound 1 and ribociclib.

[0305] Safety

[0306] Eleven participants were enrolled at dose levels 30 mg (n = 3), 60 mg (n = 3), and 120 mg (n = 3) in the dose escalation phase of the combination of compound 1 and ribociclib and at dose level n = 2 in the dose expansion phase. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached.

[0307] Table 1 lists treatment-emergent adverse events (TEAEs) that occurred in 2 or more participants. The most common TEAE was neutropenia, which was primarily attributed to ribociclib. All other TEAEs that occurred in ≥2 participants were grade 1 or 2. There was no increase in the incidence or intensity of TEAEs with increasing dose of compound 1. QT intervals (corrected according to the Fredericia formula; QTcF) were monitored. There were no increases in QTcF > grade 2 (one participant had a grade 2 increase) or increases in QTcF duration that required dose reduction or interruption of study treatment. The recommended expanded dose of compound 1 in combination with ribociclib (600 mg PO Qd, days 1–21 of a 28-day cycle) was 120 mg.

[0308] Table 1: Summary of all causal treatment-emergent adverse events (TEAEs) occurring in ≥2 subjects listed by preferred terms.

[0309]

[0310] Pharmacokinetics

[0311] Target and Endpoint

[0312] The pharmacokinetic parameters of each analyte (Compound 1, ribociclib) were determined. The analyte concentrations for each cohort, each cycle, and each day were summarized using appropriate descriptive statistics (e.g., N, arithmetic mean, standard deviation, minimum, median, maximum, coefficient of variation [CV]%, geometric mean, and CV associated with the geometric mean). The primary PK endpoints established were the following PK parameters: AUC 0-6 、AUC 0-24 、C max and T max .

[0313] Precautions for Pharmacokinetic Analysis

[0314] Subject distribution: The PK data included in this example were based on plasma concentrations of Compound 1 and ribociclib from 9 female subjects with metastatic breast cancer (MBC), who received 600 mg ribociclib tablets on an empty stomach; 3 subjects received 30 mg Compound 1 capsules, 3 subjects received 60 mg capsules, and 3 subjects received 120 mg capsules. No subjects withdrew or were terminated early. Two subjects withdrew from the study after Cycle 2. If incomplete sampling affected the PK parameters, the results were excluded from the descriptive and inferential statistics.

[0315] PK sampling: Blood samples were obtained from all subjects at the following times during Cycle 1 for PK analysis of Compound 1 in plasma: before dosing and at 0.5 hour (±15 minutes), 1 hour (±15 minutes), 2 hours (±30 minutes), 4 hours (±30 minutes), 6 hours (±30 minutes), optionally 8 hours (±30 minutes), and 24 hours (±2 hours) (which was before dosing of C1D2) on C1D1; and before dosing of C1D8 and C1D15. Blood samples were obtained from 6 out of 9 subjects at the following times for PK analysis of Compound 1 in plasma: before dosing of C2D1; before dosing and at 0.5 hour (±15 minutes), 1 hour (±15 minutes), 2 hours (±30 minutes), 4 hours (±30 minutes), 6 hours (±30 minutes), optionally 8 hours (±30 minutes), and 24 hours (±2 hours) (which was before dosing of C2D16) on C2D15; also before dosing of C3D1 and C3D15; and samples were collected before dosing of C5D1, C7D1, and C9D1. Blood samples for plasma PK analysis of ribociclib were obtained for all subjects at the same time points as Compound 1 on C1D1, C1D2, C1D8, C1D15, C2D15, and C2D16, and were collected on C3D15.

[0316] Pharmacokinetic Results

[0317] Pharmacokinetic characteristics of Compound 1: Summaries of the key pharmacokinetic parameters of Compound 1 after its co - administration with ribociclib are presented in Table 2 (Day 1) and Table 3 (steady state). Figure 1A 、 Figure 1B and Figure 1C (Day 1) and Figure 2A and Figure 2B (steady state) present the mean plasma Compound 1 concentration - time profiles after co - administration of Compound 1 with ribociclib.

[0318] Pharmacokinetic characteristics of ribociclib: Summaries of the key pharmacokinetic parameters of ribociclib after its co - administration with Compound 1 are presented in Table 4 (Day 1) and Table 5 (steady state). Figure 3 (Day 1) and Figure 4 (steady state) present dot plots of the geometric mean (geometric SD) of the plasma ribociclib pharmacokinetic parameters after co - administration of ribociclib with Compound 1.

[0319]

[0320]

[0321] Table 3 Plasma ribociclib pharmacokinetic parameters after a single oral dose of 600 mg ribociclib

[0322]

[0323] a Geometric mean (GeoCV); n, unless otherwise specified.

[0324] b Median [Min - Max]; n.

[0325] c Single - dose exposure levels of ribociclib calculated based on steady - state exposure and accumulation ratio (2.5) in the ribociclib product manuscript. The reported CV% is from the steady - state summary data of cancer patients receiving an intermittent regimen (3 - week dosing / 1 - week off) and cancer patients receiving continuous dosing (once daily for 28 days).

[0326] N / A = Not applicable.

[0327] d Average single - dose exposure levels of ribociclib digitized and calculated based on single - dose data from the Yan Ji SABCS2019 poster.

[0328] N / D = Not done.

[0329] Table 4. Steady-state plasma ribociclib dose-normalized pharmacokinetic parameters after combination of 600 mg (3-week dosing / 1-week off-dosing regimen) ribociclib with Compound 1

[0330]

[0331] a Geometric mean (GeoCV); N.

[0332] b Median [Min-Max]; n.

[0333] c 30 and 60 mg QD Compound 1.

[0334] d Pooled data from cancer patients receiving intermittent dosing regimens (3-week dosing / 1-week off) and cancer patients receiving continuous dosing (once daily for 28 days).

[0335] Pharmacokinetic Discussion and Conclusion

[0336] Compound 1

[0337] Single dose: When co-administered with 600 mg ribociclib, the single-dose exposure parameters AUC 0-6 、AUC 0-24 and C max of Compound 1 are comparable to those single-dose exposure parameters when Compound 1 is administered as a single agent. The median T max of Compound 1 administered alone or in combination with ribociclib is also comparable at each dose level studied at single dose. These results suggest that, to date, for single doses of 30, 60, and 120 mg of Compound 1, there is no significant DDI after co-administration with 600 mg ribociclib. The PK parameters for the 120 mg Compound 1 combination are within the 90% confidence interval of the geometric mean of Compound 1 monotherapy.

[0338] Steady state: When co-administered with 600 mg ribociclib, the steady-state exposure parameters AUC 0-6 、AUC 0-24 and C max of Compound 1 are comparable to those steady-state exposure parameters when Compound 1 is administered as a single agent. The median T max of Compound 1 administered alone or in combination with ribociclib is also comparable at the 30 and 60 mg Compound 1 dose levels. These results suggest that, to date, for doses of 30 and 60 mg of Compound 1, there is no significant DDI after co-administration with 600 mg ribociclib.

[0339] When compound 1 is administered in combination with 600 mg ribociclib, compound 1 PK is dose-proportional over the dose range of 30 to 120 mg.

[0340] Ribociclib

[0341] Single dose: When administered in combination with 30, 60, or 120 mg of compound 1, the single-dose exposure parameters AUC 0-24 and C max of ribociclib are comparable to those of ribociclib administered as a single agent (Novartis Pharmaceuticals Canada Inc. 2023. Available at www.ask.novartispharma.ca / download.htm?res=kisqali_scrip_e.pdf&resTitleId=1439 (accessed September 26, 2023).). The median T max of ribociclib administered alone or in combination with 30, 60, or 120 mg QD of compound 1 is comparable at single dose. These results suggest that, to date, for single-dose ribociclib, there is no significant DDI following co-administration with 30, 60, or 120 mg QD of compound 1.

[0342] Steady state: When administered in combination with 30 or 60 mg of compound 1 QD, the steady-state exposure parameters AUC 0-6 , AUC 0-24 and C max of ribociclib are comparable to those of ribociclib administered as a single agent (Novartis Pharmaceuticals Canada Inc. 2023. Available at www.ask.novartispharma.ca / download.htm?res=kisqali_scrip_e.pdf&resTitleId=1439 (accessed September 26, 2023).). These preliminary results suggest that, to date, for 3-week administration / 1-week off 600 mg QD ribociclib, there is no significant DDI following co-administration with 30 or 60 mg QD of compound 1.

Claims

1. A method of treating an estrogen receptor-mediated disease, disorder or condition in a subject, the method comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is administered in an amount of about 15 mg to about 360 mg, in combination with a composition comprising about 200 to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein Compound 1 is administered in an amount of about 30 mg to about 120 mg.

3. The method according to claim 1 or 2, wherein Compound 1 is administered in an amount of about 30 mg.

4. The method according to claim 1 or 2, wherein Compound 1 is administered in an amount of about 60 mg.

5. The method according to claim 1 or 2, wherein Compound 1 is administered in an amount of about 90 mg.

6. The method according to claim 1 or 2, wherein Compound 1 is administered in an amount of about 120 mg.

7. The method according to any one of claims 1-6, wherein ribociclib is administered in an amount of about 500 to about 700 mg.

8. The method according to any one of claims 1-7, wherein ribociclib is administered in an amount of about 600 mg.

9. The method according to any one of claims 1-8, wherein Compound 1 is administered once daily.

10. The method according to any one of claims 1-8, wherein ribociclib is administered once daily for 21 days, followed by a 7-day drug-free period.

11. The method according to any one of claims 1-10, wherein Compound 1 and ribociclib are administered simultaneously.

12. The method according to any one of claims 1-11, wherein the composition comprising Compound 1 or a pharmaceutically acceptable salt thereof is a capsule or tablet.

13. The method according to claim 12, wherein the composition comprising ribociclib or a pharmaceutically acceptable salt thereof is a capsule or tablet.

14. The method according to any one of claims 1-13, wherein the estrogen receptor-mediated disease, disorder or condition is cancer.

15. The method according to claim 14, wherein the cancer is breast cancer.

16. The method according to claim 15, wherein the cancer is HR+ / HER2- breast cancer.

17. The method according to any one of claims 14-16, wherein the cancer has metastasized to another organ.

18. The method according to claim 17, wherein the cancer has metastasized to the brain, bone, lung, or liver.

19. The method according to any one of claims 1-18, wherein the subject has previously received at least one of a CDK4 / 6 inhibitor, an aromatase inhibitor, chemotherapy, fulvestrant, or a combination thereof.

20. A method of treating a disease, disorder, or condition, the method comprising combinatorial administration of Compound 1 or a pharmaceutically acceptable salt thereof and ribociclib, wherein the improvement comprises administering about 30 mg to about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof.

21. A kit, the kit comprising a composition comprising about 30 mg to about 360 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and a composition comprising about 200 to about 800 mg of ribociclib or a pharmaceutically acceptable salt thereof.

22. The kit according to claim 21, wherein the kit comprises about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

23. The kit according to claim 21, wherein the kit comprises about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

24. The kit according to claim 21, wherein the kit comprises about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

25. The kit according to claim 21, wherein the kit comprises about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

26. The kit according to any one of claims 21-25, wherein the kit comprises about 600 mg of ribociclib or a pharmaceutically acceptable salt thereof.

27. The kit according to any one of claims 21-26, wherein the kit further comprises packaging material, the packaging material comprising a label, the label indicating that Compound 1 and ribociclib can be used to treat estrogen receptor-mediated diseases, disorders, or conditions.

28. The kit according to claim 27, wherein the estrogen receptor-mediated disease, disorder, or condition is cancer.

29. The kit according to claim 28, wherein the cancer is breast cancer.

30. The kit according to claim 29, wherein the cancer is HR+ / HER2- breast cancer.

31. The medicine box according to any one of claims 28 - 30, wherein the cancer has metastasized to another organ.

32. The medicine box according to claim 31, wherein the cancer has metastasized to the brain, bone, lung or liver.

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